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Abstract:Neuropsychiatric disorders, which are associated with stress hormone dysregulation, occurat different rates in men and women. Moreover, nowadays, preclinical and clinical evidence demonstratesthat sex and gender can lead to differences in stress responses that predispose males andfemales to different expressions of similar pathologies. In this curated review, we focus on what isknown about sex differences in classic mechanisms of stress response, such as glucocorticoid hormonesand corticotrophin-releasing factor (CRF), which are components of the hypothalamicpituitary-adrenal (HPA) axis. Then, we present sex differences in neurotransmitter levels, such as serotonin,dopamine, glutamate and GABA, as well as indices of neurodegeneration, such as amyloid βand Tau. Gonadal hormone effects, such as estrogens and testosterone, are also discussed throughoutthe review. We also review in detail preclinical data investigating sex differences caused by recentlyrecognizedregulators of stress and disease, such as the immune system, genetic and epigenetic mechanisms,as well neurosteroids. Finally, we discuss how understanding sex differences in stress responses,as well as in pharmacology, can be leveraged into novel, more efficacious therapeutics forall. Based on the supporting evidence, it is obvious that incorporating sex as a biological variable intopreclinical research is imperative for the understanding and treatment of stress-related neuropsychiatricdisorders, such as depression, anxiety and Alzheimer’s disease.